Cell-based therapy, particularly using undifferentiated cells, e.g., multipotent or pluripotent cells stem cells, presents a promising approach for regenerative medicine and tissue engineering (Short et al. Arch Med. Res. 2003 34(6):565-71, Barrilleaux et al. Tissue Eng. 2006 12(11):3007-19). In particular, bone marrow mesenchymal stem cells (MSCs), or stromal stem cells, have been shown to be beneficial in regenerating tissues of musculoskeletal (Horwitz et al. Nat. Med. 1999 March; 5(3):309-13), cardiovascular (Pittenger et al. Circ Res. 2004 95(1):9-20; Chen et al. Chin Med J (Engl). 2004 117(10):1443-8. Erratum in: Chin Med J (Engl). 2005 118(1):88; Price et al. Int J Cardiol. 2006 111(2):231-9; Wang et al. Crit. Care Med. 2007 35(11):2587-93) and neurological (Helm et al. Neurosurg Focus. 2005 15; 19(6):E13) systems. This is because of their relatively safety and easy accessibility from the donor, genetic stability, and the ability of self-renewal and differentiating into multiple lineages of cells (Pittenger et al. Science 1999 2; 284(5411):143-7; Pittenger et al. Circ Res. 2004 95(1):9-20). They also have the unique immunologically privileged status which can ignore the Human Leukocyte Antigen histocompatibility barrier (Pittenger et al. Circ Res. 2004 95(1):9-20). It is also more socially and ethically acceptable to use MSCs than embryonic stem cells.
Despite the great potential of MSC-based therapies, the functional outcomes of existing MSC therapies have not been satisfactory, at least partly due to the extremely poor engraftment rate (usually <1-2%) of MSCs at the target tissues such as hearts in the treatment of myocardial infarction (Price et al. Int J. Cardiol. 2006 111(2):231-9; Wang et al. Crit. Care Med. 2007 35(11):2587-93) and bones in the treatment of osteogenic imperfecta (Horwitz et al. Nat. Med. 1999 5(3):309-13) upon systemic injection. It is generally believed that the outcomes of MSC therapies can be further enhanced if the engraftment efficiency of human MSCs can be improved. As a result, strategies aimed to enhance the engraftment rate are important to improving the efficacy of MSCs-based therapies.
Local injection of MSCs with and without carriers is able to improve engraftment in the target tissue such as heart and intervertebral disc, but the extent of improvement is less than 5%, which is too low to generate a significant impact. Moreover, the invasiveness associated with the open surgery-based injection into inner organs such as heart and spine, and the inapplicability of local injection in diseases where multiple tissues are involved, such as osteogenic imperfecta and muscle dystrophy, prevents this approach from being widely used in regenerative medicine. Currently, no effective method exists to improve the engraftment rate of systemically supplemented MSCs.
Stem cell engraftment, sometimes used interchangeably with stem cell homing, describes the process of directing undifferentiated cells, such as MSCs, to migrate from the peripheral blood into the damaged tissues (Chamberlain et al. Stem Cells. 2007 25(11):2739-49; Chavakis et al. J Mol Cell Cardiol. 2008 45(4):514-22). The detailed mechanisms of stem cell engraftment are still unclear but directional movement of stem cells towards gradients of chemoattractants and cytokines induced by tissue injuries is known to play an important role (Ponte et al. Stem Cells. 2007 25(7):1737-45; Sordi et al. Blood. 2005 106(2):419-27; Son et al. Stem Cells. 2006 24(5):1254-64; Honczarenko et al. Stem Cells. 2006 24(4):1030-41; Ries et al. Blood. 2007 109(9):4055-63). Among all chemoattractant and receptor pairs, SDF-1 and its specific receptor CXCR4 have been shown to be most important in regulating the migration of hMSCs [Ponte et al. Stem Cells. 2007 25(7):1737-45; Dar et al. Nat. Immunol. 2005 6(10):1038-4; Dar et al. Exp Hematol. 2006 34(8):967-75; Honczarenko et al. Stem Cells. 2006 24(4):1030-41).
Several attempts have been made recently to enhance the responsiveness of MSCs towards specific chemoattractants. In particular, MSCs have been treated with chemoattractants such as SDF-1 (Shi et al. Haematologica. 2007 July; 92(7):897-904; Ponte et al. Stem Cells. 2007 25(7):1737-45), or virally transduced with chemoattractant receptor genes such as CXCR4 (Bhakta et al. Cardiovasc Revasc Med. 2006 7(1):19-24). Both methods upregulate the expression of the chemoattractant receptor on MSCs. A few other approaches include viral transduction of MSCs with anti-apoptotic genes such as Akt and telomerase to promote MSC survival (Seeger et al. Nat Clin Pract Cardiovasc Med. 2007 4 Suppl 1:S110-3) and extrinsic supplementation of chemoattractants such as SDF-1 at the injured target tissues to augment the chemoattractant signal for MSC recruitment at the injury site (Yamaguchi et al. Circulation. 2003 107(9):1322-8). Nevertheless, these approaches also have significant drawbacks such as the long term uncertainty of genetically manipulated cells, the safety issue of virally transduced cells and the poor cost-effectiveness of in vivo supplementation of chemoattractants. More importantly, none of these attempts address the heterogeneity problem of MSCs.
It is therefore an object of the invention to provide methods and compositions to promote or enhance migration, engraftment, or a combination thereof of transplanted cells, such as MSCs.